VASCULAR REACTIVITY--GENDER AND HORMONAL INFLUENCES

血管反应性——性别和荷尔蒙的影响

• 批准号: 2692676
• 负责人: SUE P DUCKLES
• 金额: $ 26.68万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2692676
• 关键词: cerebrovascular system; estrogen receptors; estrogens; gender difference; gene targeting; genetically modified animals; hemodynamics; hormone receptor; hormone regulation /control mechanism; laboratory mouse; laboratory rat; melatonin; neuroprotectants; nitric oxide synthase; polymerase chain reaction; sex cycle; sex hormones; vasomotion; western blottings

DESCRIPTION: (Adapted from the application) Actions of estrogen on function of endothelial NOS may account for cerebrovascular protection. Thus, the first hypothesis is: 1) cerebrovascular responses involving NOS are affected by estrogen. Rat middle cerebral arteries in vitro will be used to test the influence of sex and gonadal steroids, comparing males and cycling females, control or gonadectomized and steroid-replaced. The investigator will compare myogenic tone in arteries from males and females and test whether NOS inhibition abolishes gender or estrous cycle differences. Possible K+ channel involvement will be investigated. Since shear stress stimulates the activity of NOS, the PI will test whether flow induced vasodilation is influenced by estrogen status and investigate modulation by gender and gonadal steroids. As a control, effects of gender and gonadal steroids on vasodilator responses to increased extracellular K+, which does not involve NOS will be investigated. The second hypothesis is: 2) estrogen acts by regulating levels of eNOS protein. Responses to endothelial dependent vasodilators, levels of NOS protein by Western blot and NOS activity will be measured, and NOSIII-deficient mice will be studied. For the third specific aim, the PI will test whether: 3) estrogen modulates effects of melatonin by a selective action on MT2 receptor mediated vasodilation. Circadian variation in cardiovascular disease onset has been shown and estrogen regulates vascular sensitivity to melatonin. The PI will determine whether melatonin causes constriction of cerebral arteries through MT1 and dilation via MT2 receptors. Influence of sex, transmural pressure, artery size and endothelial factors will be investigated. The PI will also test whether dilator responses via MT2 receptors are preferentially enhanced by estrogen exposure and using RT-PCR whether gonadal hormones alter expression of melatonin receptor subtypes. The final hypothesis is: 4) effects of estrogen are mediated by the classical estrogen receptor Estrogen receptor antagonists and estrogen receptor knockout mice will be used to test whether this receptor accounts for effects on cerebrovascular reactivity. Given the enormous impact of hormone replacement therapy, knowledge of the effects of gonadal steroids and melatonin on the cerebral circulation is essential.

描述：（改编自申请）雌激素对功能的作用 内皮NOS的增加可能对脑血管有保护作用。 因此， 第一个假设是： 1) 涉及 NOS 的脑血管反应是 受雌激素影响。 体外大鼠大脑中动脉将用于 测试性和性腺类固醇的影响，比较男性和骑自行车 女性，对照或进行性腺切除和类固醇替代。 调查员 将比较男性和女性动脉的肌源性张力并进行测试 NOS 抑制是否消除了性别或动情周期差异。 将调查可能的 K+ 通道参与情况。 由于剪切应力 刺激NOS活性，PI将测试是否诱导流量 血管舒张受雌激素状态的影响，并研究其调节作用 性别和性腺类固醇。 作为对照，性别和性腺的影响 类固醇对血管扩张剂对细胞外 K+ 增加的反应的影响，这确实 不涉及NOS将受到调查。 第二个假设是：2) 雌激素通过调节 eNOS 蛋白的水平发挥作用。 回应 内皮依赖性血管扩张剂，Western blot 检测 NOS 蛋白水平 并测量 NOS 活性，并检测 NOSIII 缺陷小鼠 研究过。 对于第三个具体目标，PI 将测试是否：3) 雌激素 通过选择性作用 MT2 受体来调节褪黑激素的作用 介导的血管舒张。 心血管疾病发病的昼夜节律变化 已被证明雌激素可调节血管对褪黑激素的敏感性。 PI将确定褪黑激素是否会导致脑收缩 通过 MT1 受体传导动脉并通过 MT2 受体扩张。 性别的影响， 跨壁压、动脉大小和内皮因素 调查了。 PI 还将测试扩张器是否通过 MT2 做出响应 受体优先通过雌激素暴露和使用 RT-PCR 增强 性腺激素是否会改变褪黑激素受体亚型的表达。 最终的假设是：4）雌激素的作用是由 经典雌激素受体 雌激素受体拮抗剂和雌激素 受体敲除小鼠将被用来测试该受体是否占 对脑血管反应性的影响。 鉴于其巨大影响 激素替代疗法，性腺类固醇影响的知识 而褪黑激素对大脑循环至关重要。